Many substituted phenols are difficult to synthesize. One common reaction utilizes the replacement of a halogen atom in a substituted chlorobenzene with base. As stated in Billman and Cleland, Methods of Synthesis in Organic Chemistry (Edwards Brothers, Inc., Ann Arbor, Mich. 1954 edition), "[i]t is very difficult to remove a halogen atom from the benzene ring unless there are meta-directing groups in the ortho and/or para positions with respect to the halogen atom." In other words, a misoriented chlorine atom, as in picryl chloride can readily be replaced by hydroxyl using aqueous sodium hydroxide to yield the corresponding phenol, picric acid. Conversion of chlorobenzene, in which there is no misoriented, meta-directing group, to phenol requires the most stringent reaction conditions; for example, reaction temperatures of 300.degree. C., high pressure and flake sodium hydroxide or other alkali. Another method of preparing phenols is by the fusion of an alkali sulfonate or sulfonic acid with sodium hydroxide, also a reaction requiring extreme conditions.
Obviously, reaction conditions which involve extremes of temperature and pressure plus strong alkali are not suitable for the preparation of many substituted phenols and in particular trifluoromethylphenol, since the trifluoromethyl group would be expected to undergo reaction under such extreme conditions.
A second common method of preparing phenols is by the hydrolysis of a substituted phenyldiazonium salt. This synthetic procedure presupposes the preparation of a properly substituted nitrobenzene in which the nitro group is successively reduced to an aniline, the amine group diazotized and the diazonium salt decomposed to yield a phenol. This reaction is not suitable for the preparation of either ortho or para trifluoromethyl phenols since, in the requisite starting material, direct substitution does not produce the desired nitro compound since the trifluoromethyl group is a meta directing group. The trifluoromethyl group can, of course, be prepared from the corresponding carboxylic acid. But again, the carboxylic acid group is a meta directing group and it is difficult to prepare o-or p-nitrobenzoic acids.
Another procedure that has been employed for the preparation of p-trifluoromethylphenol, in particular, has been the chlorination of p-cresol to yield p-trichloromethylphenol. The chlorine atoms can be replaced by fluorine by reaction with antimony pentafluoride. This reaction is a laboratory scale procedure and can not be adapted to commercial production --see R. G. Jones, J. Am. Chem. Soc., 69, 2346 (1947).
Yet another procedure, replacement of the carboxylic acid group in salicylic acid (o-hydroxybenzoic acid) with a trifluoromethyl group by reacting with SF.sub.4 plus HF, is also difficult to adapt to a commercial scale because of the problem of handling SF.sub.4 although the yields of o-hydroxy compound are reasonable. The reaction, however does not proceed with as good yields where the p-hydroxybenzoic acid is concerned and this acid is, itself, a more difficult to obtain than salicylic acid.
Another approach to the problem of devising synthetic procedures for the preparation of difficultly synthesizable phenols might be termed an indirect approach. In this type of procedure, a given chlorobenzene is nitrated ortho to the chloro group; thus increasing its lability to hydrolytic replacement. Then, the nitro group is removed by the steps of reduction, diazotization of the resulting aniline, and replacement of the azido group by hydrogen. This indirect approach is illustrated by the synthesis of p-trifluoromethylphenol described by Lavagnino et al., Org. Prep. Proced. Int. 9, 96 (1977) which was, until the present invention, the best published method for preparing that compound.
It has recently been found by Molloy and Schmiegel that the 3-(trifluoromethylphenoxy)-3-phenylpropylamines, including the primary amines, the secondary N-methyl amines, and the tertiary N,N-dimethylamines are specific inhibitors of the uptake of serotonin, indicating their potential use as psychotrophic drugs in the treatment of depression (see U.S. Pat. No. 4,018,895). These compounds are prepared according to the following general scheme. The keto group of .beta.-diethylaminopropiophenone is reduced to a secondary alcohol with diborane. The hydroxy group is replaced by chlorine using HCl and the chloro compound reacted with the sodium salt of the particular trifluoromethylphenol to yield the desired compound. The corresponding N-methyl compounds are prepared by removal of one of the methyl groups from the N,N-dimethyl derivative using cyanogen bromide. The corresponding primary amines are prepared by a procedure involving the reaction of the desired trifluoromethylphenol sodium salt with 3-chloro-1-bromopropylbenzene. The sodium salt of the phenol reacts preferentially with the bromo group to yield a 3-chloro-1-(trifluoromethylphenoxy)propylbenzene. The chloro compound is then reacted with sodium azide and the resulting azido compound reduced to the primary amine. The same reaction scheme serves to prepare the N-methyl secondary amines by reacting the 3-chloro-1-(trifluoromethylphenoxy)propylbenzene with methylamine instead of NaN.sub.3.
Each of the above reaction schemes requires the use of a particular trifluoromethylphenol. It is an object of this invention to provide a new and useful procedure for the preparation of the 3-trifluoromethylphenols, which procedure is well adapted to commercial use. In particular, it is an object of this invention to provide a method for preparing p-trifluoromethylphenol from the relatively cheap intermediate, p-trifluoromethylchlorobenzene. Other objects of this invention will become apparent from the following specification.